MSGID: 1:317/3 6274a4df   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Breaking the shield that protects pancreatic cancer from immunotherapy   
      
      
     Date:   
         May 5, 2022   
     Source:   
         UT Southwestern Medical Center   
     Summary:   
         Scar-like cells that make up a sizable portion of malignant   
         pancreatic tumors and shield these cancers from immune attack are   
         derived from mesothelial cells that line tissues and organs, a new   
         study suggests. The findings could offer a new strategy to fight   
         pancreatic cancer, a deadly disease for which no truly effective   
         treatments exist.   
      
      
      
   FULL STORY   
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   Scar-like cells that make up a sizable portion of malignant pancreatic   
   tumors and shield these cancers from immune attack are derived from   
   mesothelial cells that line tissues and organs, a new study led by UT   
   Southwestern researchers suggests. The findings, published in Cancer   
   Cell, could offer a new strategy to fight pancreatic cancer, a deadly   
   disease for which no truly effective treatments exist.   
      
      
   ==========================================================================   
   "By targeting antigen-presenting cancer-associated fibroblasts, we might   
   someday be able significantly to enhance the activity of immune therapy in   
   pancreatic cancer patients," said Huocong Huang, M.D., Ph.D., Instructor   
   of Surgery at UTSW. Dr. Huang co-led the study with Rolf A. Brekken,   
   Ph.D., Professor of Surgery, Pharmacology, and in UTSW's Hamon Center   
   for Therapeutic Oncology Research, and a member of the Harold C. Simmons   
   Comprehensive Cancer Center.   
      
   According to the American Cancer Society, about 56,000 people in the   
   U.S. are diagnosed each year with pancreatic ductal adenocarcinoma (PDA),   
   the most common form of pancreatic cancer. Currently the fourth-leading   
   cause of cancer- related deaths in this country, it's projected to   
   become the second-leading cause by 2030. Despite decades of research,   
   the prognosis for PDA remains dismal, with only 10% of patients surviving   
   five years past diagnosis.   
      
   Researchers have long known that cells called cancer-associated   
   fibroblasts (CAFs) make up a significant portion of pancreatic   
   tumors. Much like the fibroblasts that compose scar tissue, CAFs make   
   pancreatic tumors dense and tough, preventing chemotherapies and other   
   treatments from readily reaching cancer cells. Although scientists had   
   considered these pancreatic CAFs to be a uniform population, Dr. Huang   
   explained, he and his colleagues in the Brekken lab showed in an earlier   
   study in 2019 that these cells fall into three categories. One of these   
   is a subtype known as antigen-presenting CAFs (apCAFs), which interact   
   with immune cells by displaying proteins called antigens on their surface.   
      
   To determine how apCAFs contribute to PDA progression, Dr. Huang,   
   Dr. Brekken, and their colleagues used a technique known as lineage   
   tracing to learn how these cells arise as a normal pancreas develops   
   cancer. Their findings showed that apCAFs originate from mesothelial   
   cells, which form a protective membrane that lines organs, body cavities,   
   and tissues.   
      
   Further experiments showed that the antigens on the surface of apCAFs   
   could convert immune cells called T-cells into a subset known as   
   regulatory T-cells (Tregs), which shield tumors from immune attack. When   
   the researchers dosed mice carrying pancreatic tumors with antibodies   
   against mesothelin, a protein unique to mesothelial cells, the conversion   
   to Tregs was blocked, leaving tumors more vulnerable to an anti-tumor   
   immune response.   
      
   Although more research is necessary in animal models, Dr. Huang noted   
   that it may eventually be possible to employ a similar strategy to treat   
   PDA in humans by administering anti-mesothelin antibodies in combination   
   with immunotherapies that stimulate the immune system to fight cancers.   
      
   Dr. Brekken, an Effie Marie Cain Research Scholar, noted that the study   
   clarifies the origin and function of apCAFs in PDA but has implications   
   beyond pancreatic cancer, an area that Dr. Huang will continue to   
   investigate.   
      
   Other UTSW researchers who contributed to this study include Yuqing Zhang,   
   Debolina Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu   
   Gu, and Ravikanth Maddipati.   
      
   This study was funded by the National Institutes of Health (K99 CA252009,   
   R01 CA243577 and U54 CA210181 Project 2), the Effie Marie Cain Fellowship,   
   and the Jean Shelby Fund for Cancer Research at the Communities Foundation   
   of Texas.   
      
      
   ==========================================================================   
   Story Source: Materials provided by UT_Southwestern_Medical_Center. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana N. Pradhan,   
      Debolina   
         Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu   
         Gu, Ravikanth Maddipati, So"ren Mu"ller, Shannon J. Turley, Rolf   
         A. Brekken.   
      
         Mesothelial cell-derived antigen-presenting cancer-associated   
         fibroblasts induce expansion of regulatory T cells in pancreatic   
         cancer. Cancer Cell, 2022; DOI: 10.1016/j.ccell.2022.04.011   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220505143826.htm   
      
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